2-Phenyl or 2-(substituted phenyl)-5-(or 6)-benzoxazolylalkanoic acids, highly useful anti-inflammatory agents, are disclosed and claimed in U.S. Pat. No. 3,912,748. One of the most active of these acids, dl-.alpha.-(2-[4-chlorophenyl]-5-benzoxazolyl)propionic acid, also named dl-2-(4-chlorophenyl)-.alpha.-methyl-5-benzoxazolylacetic acid, has been given the generic name "benoxaprofen" and is currently undergoing a clinical trial as a non-steroidal anti-inflammatory agent of particular value in the treatment of rheumatoid arthritis and related diseases. The chemistry and pharmacology of these 2-aryl-5-benzoxazolyl alkanoic acids is to be found in J. Med. Chem., 18, 53 (1975). In general, benzoxazolyl alkanoic acids are prepared by hydrolysis of the corresponding nitrile followed by a purification step involving recrystallization from an organic solvent. Benoxaprofen prepared by such a procedure has been found to crystallize from organic solvents in two different forms, known as Form I and Form II. Crystalline Form II is considerably more stable than Form I on being aged at relatively high temperature, and this increased stability carries over into pharmaceutical formulations containing the compound.
It has been known to purify benzoic and terephthalic acids obtained by the hydrolysis of their respective nitriles by formation of the ammonium salt, separation of the thus formed ammonium salt from impurities followed by decomposition by heat of the ammonium salt to yield the free acid and gaseous ammonia as a volatile byproduct. (See for example, U.S. Pat. No. 3,876,691 or U.S. Pat. No. 3,849,489).
It is an object of this invention to provide a method for purifying dl-2-(4-chlorophenyl)acid-.alpha.-methyl-5-benzoxazolylacetic acid and related compounds which yields the desired compound in a high degree of purity employing a relatively simple chemical process which does not require expensive equipment, and furnishes benoxaprofen in the desirable crystalline Form II when used to purify this compound.